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  • 1. Bentley, Katie
    et al.
    Franco, Claudio Areias
    Philippides, Andrew
    Blanco, Raquel
    Dierkes, Martina
    Gebala, Veronique
    Stanchi, Fabio
    Jones, Martin
    Aspalter, Irene M.
    Cagna, Guiseppe
    Weström, Simone
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Claesson-Welsh, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Vestweber, Dietmar
    Gerhardt, Holger
    The role of differential VE-cadherin dynamics in cell rearrangement during angiogenesis2014In: Nature Cell Biology, ISSN 1465-7392, E-ISSN 1476-4679, Vol. 16, no 4, p. 309-321Article in journal (Refereed)
    Abstract [en]

    Endothelial cells show surprising cell rearrangement behaviour during angiogenic sprouting; however, the underlying mechanisms and functional importance remain unclear. By combining computational modelling with experimentation, we identify that Notch/VEGFR-regulated differential dynamics of VE-cadherin junctions drive functional endothelial cell rearrangements during sprouting. We propose that continual flux in Notch signalling levels in individual cells results in differential VE-cadherin turnover and junctional-cortex protrusions, which powers differential cell movement. In cultured endothelial cells, Notch signalling quantitatively reduced junctional VE-cadherin mobility. In simulations, only differential adhesion dynamics generated long-range position changes, required for tip cell competition and stalk cell intercalation. Simulation and quantitative image analysis on VE-cadherin junctional patterning in vivo identified that differential VE-cadherin mobility is lost under pathological high VEGF conditions, in retinopathy and tumour vessels. Our results provide a mechanistic concept for how cells rearrange during normal sprouting and how rearrangement switches to generate abnormal vessels in pathologies.

  • 2.
    Bergsten, Erika
    et al.
    Ludwig Institute for Cancer Research, Stockholm Branch, PO Box 240, S-171 77 Stockholm, Sweden .
    Uutela, Marko
    Molecular/Cancer Biology Laboratory, Haartman Institute, University of Helsinki, PO Box 21 (Haartmaninkatu 3), SF-00014 Helsinki, Finland .
    Li, Xuri
    Ludwig Institute for Cancer Research, Stockholm Branch, PO Box 240, S-171 77 Stockholm, Sweden .
    Pietras, Kristian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Ludwig Institute for Cancer Research.
    Östman, Arne
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Ludwig Institute for Cancer Research.
    Heldin, Carl-Henrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Ludwig Institute for Cancer Research.
    Alitalo, Kari
    Molecular/Cancer Biology Laboratory, Haartman Institute, University of Helsinki, PO Box 21 (Haartmaninkatu 3), SF-00014 Helsinki, Finland .
    Eriksson, Ulf
    Ludwig Institute for Cancer Research, Stockholm Branch, PO Box 240, S-171 77 Stockholm, Sweden .
    PDGF-D is a specific, protease-activated ligand for the PDGF beta-receptor2001In: Nature Cell Biology, ISSN 1465-7392, E-ISSN 1476-4679, Vol. 3, no 5, p. 512-516Article in journal (Refereed)
    Abstract [en]

    The term 'platelet-derived growth factor' (PDGF) refers to a family of disulphide-bonded dimeric isoforms that are important for growth, survival and function in several types of connective tissue cell. So far, three different PDGF chains have been identified - the classical PDGF-A and PDGF-B and the recently identified PDGF-C. PDGF isoforms (PDGF-AA, AB, BB and CC) exert their cellular effects by differential binding to two receptor tyrosine kinases. The PDGF alpha-receptor (PDGFR-alpha) binds to all three PDGF chains, whereas the beta-receptor (PDGFR-beta) binds only to PDGF-B. Gene-targeting studies using mice have shown that the genes for PDGF-A and PDGF-B, as well as the two PDGFR genes, are essential for normal development. Furthermore, overexpression of PDGFs is linked to different pathological conditions, including malignancies, atherosclerosis and fibroproliferative diseases. Here we have identify and characterize a fourth member of the PDGF family, PDGF-D. PDGF-D has a two-domain structure similar to PDGF-C and is secreted as a disulphide-linked homodimer, PDGF-DD. Upon limited proteolysis, PDGF-DD is activated and becomes a specific agonistic ligand for PDGFR-beta. PDGF-DD is the first known PDGFR-beta-specific ligand, and its unique receptor specificity indicates that it may be important for development and pathophysiology in several organs.

  • 3.
    Costa, Guilherme
    et al.
    Univ Manchester, Fac Biol Med & Hlth, Michael Smith Bldg,Oxford Rd, Manchester M13 9PT, Lancs, England..
    Harrington, Kyle I.
    Harvard Med Sch, Beth Israel Deaconess Med Ctr, Vasc Biol Res Ctr, Computat Biol Lab, Boston, MA 02215 USA..
    Lovegrove, Holly E.
    Univ Manchester, Fac Biol Med & Hlth, Michael Smith Bldg,Oxford Rd, Manchester M13 9PT, Lancs, England..
    Page, Donna J.
    Univ Manchester, Fac Biol Med & Hlth, Michael Smith Bldg,Oxford Rd, Manchester M13 9PT, Lancs, England..
    Chakravartula, Shilpa
    Harvard Med Sch, Beth Israel Deaconess Med Ctr, Vasc Biol Res Ctr, Computat Biol Lab, Boston, MA 02215 USA..
    Bentley, Katie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. Harvard Med Sch, Beth Israel Deaconess Med Ctr, Vasc Biol Res Ctr, Computat Biol Lab, Boston, MA 02215 USA..
    Herbert, Shane P.
    Univ Manchester, Fac Biol Med & Hlth, Michael Smith Bldg,Oxford Rd, Manchester M13 9PT, Lancs, England..
    Asymmetric division coordinates collective cell migration in angiogenesis2016In: Nature Cell Biology, ISSN 1465-7392, E-ISSN 1476-4679, Vol. 18, no 12, p. 1292-+Article in journal (Refereed)
    Abstract [en]

    The asymmetric division of stem or progenitor cells generates daughters with distinct fates and regulates cell diversity during tissue morphogenesis. However, roles for asymmetric division in other more dynamic morphogenetic processes, such as cell migration, have not previously been described. Here we combine zebrafish in vivo experimental and computational approaches to reveal that heterogeneity introduced by asymmetric division generates multicellular polarity that drives coordinated collective cell migration in angiogenesis. We find that asymmetric positioning of the mitotic spindle during endothelial tip cell division generates daughters of distinct size with discrete 'tip' or 'stalk' thresholds of pro-migratory Vegfr signalling. Consequently, post-mitotic Vegfr asymmetry drives Dll4/Notch-independent self-organization of daughters into leading tip or trailing stalk cells, and disruption of asymmetry randomizes daughter tip/stalk selection. Thus, asymmetric division seamlessly integrates cell proliferation with collective migration, and, as such, may facilitate growth of other collectively migrating tissues during development, regeneration and cancer invasion.

  • 4.
    Gängel, Konstantin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Betsholtz, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Cancer and Vascular Biology.
    Endocytosis regulates VEGF signalling during angiogenesis2013In: Nature Cell Biology, ISSN 1465-7392, E-ISSN 1476-4679, Vol. 15, no 3, p. 233-235Article in journal (Other academic)
    Abstract [en]

    Endocytosis has proved to be a versatile mechanism regulating diverse cellular processes, ranging from nutrient uptake to intracellular signal transduction. New work reinforces the importance of endocytosis for VEGF receptor signalling and angiogenesis in the developing eye, and describes a mechanism for its differential regulation in angiogenic versus quiescent endothelial cells.

  • 5.
    Haglund, Kaisa
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
    Sigismund, Sara
    Polo, Simona
    Szymkiewicz, Iwona
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
    Di Fiore, Pier Paolo
    Dikic, Ivan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
    Multiple monoubiquitination of RTKs is sufficient for their endocytosis and degradation2003In: Nature Cell Biology, ISSN 1465-7392, E-ISSN 1476-4679, Vol. 5, no 5, p. 461-466Article in journal (Refereed)
    Abstract [en]

    Many cellular proteins are post-translationally modified by the addition of a single ubiquitin or a polyubiquitin chain. Among these are receptor tyrosine kinases (RTKs), which undergo ligand-dependent ubiquitination. The ubiquitination of RTKs has become recognized as an important signal for their endocytosis and degradation in the lysosome; however, it is not clear whether ubiquitination itself is sufficient for this process or simply participates in its regulation. The issue is further complicated by the fact that RTKs are thought to be polyubiquitinated - a modification that is linked to protein degradation by the proteasome. By contrast, monoubiquitination has been associated with diverse proteasome-independent cellular functions including intracellular protein movement. Here we show that the epidermal growth factor and platelet-derived growth factor receptors are not polyubiquitinated but rather are monoubiquitinated at multiple sites after their ligand-induced activation. By using different biochemical and molecular genetics approaches, we show that a single ubiquitin is sufficient for both receptor internalization and degradation. Thus, monoubiquitination is the principal signal responsible for the movement of RTKs from the plasma membrane to the lysosome.

  • 6.
    Jin, Yi
    et al.
    Karolinska Inst, Dept Med Biochem & Biophys, Scheeles Vag 2, S-17177 Stockholm, Sweden..
    Muhl, Lars
    Karolinska Inst, Dept Med Biochem & Biophys, Scheeles Vag 2, S-17177 Stockholm, Sweden..
    Burmakin, Mikhail
    Karolinska Inst, Dept Med Biochem & Biophys, Scheeles Vag 2, S-17177 Stockholm, Sweden..
    Wang, Yixin
    Karolinska Inst, Dept Med Biochem & Biophys, Scheeles Vag 2, S-17177 Stockholm, Sweden..
    Duchez, Anne-Claire
    Karolinska Inst, Dept Med Biochem & Biophys, Scheeles Vag 2, S-17177 Stockholm, Sweden..
    Betsholtz, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology. Karolinska Inst, ICMC, Blickagangen 6, SE-14157 Huddinge, Sweden..
    Arthur, Helen M.
    Newcastle Univ, Inst Med Genet, Int Ctr Life, Newcastle Upon Tyne NE1 3BZ, Tyne & Wear, England..
    Jakobsson, Lars
    Karolinska Inst, Dept Med Biochem & Biophys, Scheeles Vag 2, S-17177 Stockholm, Sweden..
    Endoglin prevents vascular malformation by regulating flow-induced cell migration and specification through VEGFR2 signalling2017In: Nature Cell Biology, ISSN 1465-7392, E-ISSN 1476-4679, Vol. 19, no 6, p. 639-652Article in journal (Refereed)
    Abstract [en]

    Loss-of-function (LOF) mutations in the endothelial cell (EC)-enriched gene endoglin (ENG) cause the human disease hereditary haemorrhagic telangiectasia-1, characterized by vascular malformations promoted by vascular endothelial growth factor A (VEGFA). How ENG deficiency alters EC behaviour to trigger these anomalies is not understood. Mosaic ENG deletion in the postnatal mouse rendered Eng LOF ECs insensitive to flow-mediated venous to arterial migration. Eng LOF ECs retained within arterioles acquired venous characteristics and secondary ENG-independent proliferation resulting in arteriovenous malformation (AVM). Analysis following simultaneous Eng LOF and overexpression (OE) revealed that ENG OE ECs dominate tip-cell positions and home preferentially to arteries. ENG knockdown altered VEGFA-mediated VEGFR2 kinetics and promoted AKT signalling. Blockage of PI(3)K/AKT partly normalized flow-directed migration of ENG LOF ECs in vitro and reduced the severity of AVM in vivo. This demonstrates the requirement of ENG in flow-mediated migration and modulation of VEGFR2 signalling in vascular patterning.

  • 7. Kalinina, Iana
    et al.
    Nandi, Amitabha
    Delivani, Petrina
    Chacón, Mariola R
    Klemm, Anna H
    Ramunno-Johnson, Damien
    Krull, Alexander
    Lindner, Benjamin
    Pavin, Nenad
    Tolić-Nørrelykke, Iva M
    Pivoting of microtubules around the spindle pole accelerates kinetochore capture.2013In: Nature Cell Biology, ISSN 1465-7392, E-ISSN 1476-4679, Vol. 15, no 1, p. 82-7Article in journal (Refereed)
    Abstract [en]

    During cell division, spindle microtubules attach to chromosomes through kinetochores, protein complexes on the chromosome. The central question is how microtubules find kinetochores. According to the pioneering idea termed search-and-capture, numerous microtubules grow from a centrosome in all directions and by chance capture kinetochores. The efficiency of search-and-capture can be improved by a bias in microtubule growth towards the kinetochores, by nucleation of microtubules at the kinetochores and at spindle microtubules, by kinetochore movement, or by a combination of these processes. Here we show in fission yeast that kinetochores are captured by microtubules pivoting around the spindle pole, instead of growing towards the kinetochores. This pivoting motion of microtubules is random and independent of ATP-driven motor activity. By introducing a theoretical model, we show that the measured random movement of microtubules and kinetochores is sufficient to explain the process of kinetochore capture. Our theory predicts that the speed of capture depends mainly on how fast microtubules pivot, which was confirmed experimentally by speeding up and slowing down microtubule pivoting. Thus, pivoting motion allows microtubules to explore space laterally, as they search for targets such as kinetochores.

  • 8. Karkkainen, Marika J
    et al.
    Mäkinen, Taija
    Alitalo, Kari
    Lymphatic endothelium: a new frontier of metastasis research.2002In: Nature Cell Biology, ISSN 1465-7392, E-ISSN 1476-4679, Vol. 4, no 1Article in journal (Refereed)
    Abstract [en]

    The vascular endothelium is a dynamic tissue with many active functions. Until recently, endothelial cell (EC) biology studies have used cultured ECs from various organs; these cell lines are considered representative of the blood vascular endothelium. Very few lymphatic EC lines have been available, and these were derived from lymphatic tumours or large collecting lymphatic ducts. In the past, lymphatic vessels were defined largely by the lack of erythrocytes in their lumen, a lack of junctional complexes and the lack of a well-defined basement membrane. Now that lymphatic-specific vascular endothelial growth factors (VEGF-C and VEGF-D) and molecular cell surface markers such as the VEGFR-3 receptor have been identified, this definition needs to be updated. Recent developments have highlighted the importance of lymphatic ECs, and they could become the next focus for angiogenesis and metastasis research.

  • 9.
    Sorrentino, Alessandro
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Ludwig Institute for Cancer Research.
    Thakur, Noopur
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Ludwig Institute for Cancer Research.
    Grimsby, Susanne
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Ludwig Institute for Cancer Research.
    Marcusson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Ludwig Institute for Cancer Research.
    von Bulow, Verena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Ludwig Institute for Cancer Research.
    Schuster, Norbert
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Ludwig Institute for Cancer Research.
    Zhang, Shouting
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Ludwig Institute for Cancer Research.
    Heldin, Carl-Henrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Ludwig Institute for Cancer Research.
    Landström, Maréne
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Ludwig Institute for Cancer Research. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    The type I TGF-beta receptor engages TRAF6 to activate TAK1 in a receptor kinase-independent manner2008In: Nature Cell Biology, ISSN 1465-7392, E-ISSN 1476-4679, Vol. 10, no 10, p. 1199-1207Article in journal (Refereed)
    Abstract [en]

    Transforming growth factor-β (TGF-β) is a multifunctional cytokine that regulates embryonic development and tissue homeostasis; however, aberrations of its activity occur in cancer. TGF-β signals through its Type II and Type I receptors (TβRII and TβRI) causing phosphorylation of Smad proteins. TGF-β-associated kinase 1 (TAK1), a member of the mitogen-activated protein kinase kinase kinase (MAPKKK) family, was originally identified as an effector of TGF-β-induced p38 activation. However, the molecular mechanisms for its activation are unknown. Here we report that the ubiquitin ligase (E3) TRAF6 interacts with a consensus motif present in TβRI. The TβRI–TRAF6 interaction is required for TGF-β-induced autoubiquitylation of TRAF6 and subsequent activation of the TAK1–p38/JNK pathway, which leads to apoptosis. TβRI kinase activity is required for activation of the canonical Smad pathway, whereas E3 activity of TRAF6 regulates the activation of TAK1 in a receptor kinase-independent manner. Intriguingly, TGF-β-induced TRAF6-mediated Lys 63-linked polyubiquitylation of TAK1 Lys 34 correlates with TAK1 activation. Our data show that TGF-β specifically activates TAK1 through interaction of TβRI with TRAF6, whereas activation of Smad2 is not dependent on TRAF6.

  • 10. Tammela, Tuomas
    et al.
    Zarkada, Georgia
    Nurmi, Harri
    Jakobsson, Lars
    Heinolainen, Krista
    Tvorogov, Denis
    Zheng, Wei
    Franco, Claudio A
    Murtomäki, Aino
    Aranda, Evelyn
    Miura, Naoyuki
    Ylä-Herttuala, Seppo
    Fruttiger, Marcus
    Mäkinen, Taija
    Eichmann, Anne
    Pollard, Jeffrey W
    Gerhardt, Holger
    Alitalo, Kari
    VEGFR-3 controls tip to stalk conversion at vessel fusion sites by reinforcing Notch signalling.2011In: Nature Cell Biology, ISSN 1465-7392, E-ISSN 1476-4679, Vol. 13, no 10Article in journal (Refereed)
    Abstract [en]

    Angiogenesis, the growth of new blood vessels, involves specification of endothelial cells to tip cells and stalk cells, which is controlled by Notch signalling, whereas vascular endothelial growth factor receptor (VEGFR)-2 and VEGFR-3 have been implicated in angiogenic sprouting. Surprisingly, we found that endothelial deletion of Vegfr3, but not VEGFR-3-blocking antibodies, postnatally led to excessive angiogenic sprouting and branching, and decreased the level of Notch signalling, indicating that VEGFR-3 possesses passive and active signalling modalities. Furthermore, macrophages expressing the VEGFR-3 and VEGFR-2 ligand VEGF-C localized to vessel branch points, and Vegfc heterozygous mice exhibited inefficient angiogenesis characterized by decreased vascular branching. FoxC2 is a known regulator of Notch ligand and target gene expression, and Foxc2(+/-);Vegfr3(+/-) compound heterozygosity recapitulated homozygous loss of Vegfr3. These results indicate that macrophage-derived VEGF-C activates VEGFR-3 in tip cells to reinforce Notch signalling, which contributes to the phenotypic conversion of endothelial cells at fusion points of vessel sprouts.

  • 11. van der Laan, Martin
    et al.
    Meinecke, Michael
    Dudek, Jan
    Hutu, Dana P.
    Lind, Maria
    Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Physiology and Developmental Biology, Comparative Physiology.
    Perschil, Inge
    Guiard, Bernard
    Wagner, Richard
    Pfanner, Nikolaus
    Rehling, Peter
    Motor-free mitochondrial presequence translocase drives membrane integration of preproteins2007In: Nature Cell Biology, ISSN 1465-7392, E-ISSN 1476-4679, Vol. 9, no 10, p. 1152-1159Article in journal (Refereed)
    Abstract [en]

    The mitochondrial inner membrane is the central energy-converting membrane of eukaryotic cells. the electrochemical proton gradient generated by the respiratory chain drives the ATP synthase. to maintain this proton-motive force, the inner membrane forms a tight barrier and strictly controls the translocation of ions(1). However, the major preprotein transport machinery of the inner membrane, termed the presequence translocase, translocates polypeptide chains into or across the membrane(2-9). Different views exist of the molecular mechanism of the translocase, in particular of the coupling with the import motor of the matrix(8,10,11). Wehave reconstituted preprotein transport into the mitochondrial inner membrane by incorporating the purified presequence translocase into cardiolipin-containing liposomes. We show that the motor-free form of the presequence translocase integrates preproteins into the membrane. the reconstituted presequence translocase responds to targeting peptides and mediates voltage-driven preprotein translocation, lateral release and insertion into the lipid phase. thus, the minimal system for preprotein integration into the mitochondrial inner membrane is the presequence translocase, a cardiolipin-rich membrane and a membrane potential.

  • 12.
    Vincent, Theresa
    et al.
    Ludwig Institute for Cancer Research, Stockholm Branch, 17177 Stockholm, Sweden.
    Neve, Etienne P. A.
    Ludwig Institute for Cancer Research, Stockholm Branch, 17177 Stockholm, Sweden.
    Johnson, Jill R.
    Department of Cell and Molecular Biology, Karolinska Institute, 17177 Stockholm, Sweden.
    Kukalev, Alexander
    Department of Cell and Molecular Biology, Karolinska Institute, 17177 Stockholm, Sweden.
    Rojo, Federico
    Oncology Department, Programa de Recerca en Càncer, IMIM-Hospital del Mar, 08003 Barcelona, Spain.
    Albanell, Joan
    Oncology Department, Programa de Recerca en Càncer, IMIM-Hospital del Mar, 08003 Barcelona, Spain.
    Pietras, Kristian
    Department of Biochemistry and Biophysics, Matrix Division, Karolinska Institute, 17177 Stockholm, Sweden.
    Virtanen, Ismo
    Institute of Biomedicine/Anatomy, FI‑00014, University of Helsinki, Finland.
    Philipson, Lennart
    Department of Cell and Molecular Biology, Karolinska Institute, 17177 Stockholm, Sweden.
    Leopold, Philip L.
    Department of Chemistry, Chemical Biology, and Biomedical Engineering, Stevens Institute of Technology, New Jersey 07030, USA.
    Crystal, Ronald G.
    Department of Genetic Medicine, Weill Medical College of Cornell University, New York 10065, USA.
    de Herreros, Antonio Garcia
    Oncology Department, Programa de Recerca en Càncer, IMIM-Hospital del Mar, 08003 Barcelona, Spain.
    Moustakas, Aristidis
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm , Ludwig Institute for Cancer Research.
    Pettersson, Ralf F.
    Ludwig Institute for Cancer Research, Stockholm Branch, 17177 Stockholm, Sweden.
    Fuxe, Jonas
    Ludwig Institute for Cancer Research, Stockholm Branch, 17177 Stockholm, Sweden.
    A SNAIL1–SMAD3/4 transcriptional repressor complex promotes TGF‑β mediated epithelial–mesenchymal transition2009In: Nature Cell Biology, ISSN 1465-7392, E-ISSN 1476-4679, Vol. 11, no 8, p. 943-950Article in journal (Refereed)
    Abstract [en]

    Epithelial-mesenchymal transition (EMT) is essential for organogenesis and is triggered during carcinoma progression to an invasive state. Transforming growth factor-β (TGF-β) cooperates with signalling pathways, such as Ras and Wnt, to induce EMT, but the molecular mechanisms are not clear. Here, we report that SMAD3 and SMAD4 interact and form a complex with SNAIL1, a transcriptional repressor and promoter of EMT. The SNAIL1-SMAD3/4 complex was targeted to the gene promoters of CAR, a tight-junction protein, and E-cadherin during TGF-β-driven EMT in breast epithelial cells. SNAIL1 and SMAD3/4 acted as co-repressors of CAR, occludin, claudin-3 and E-cadherin promoters in transfected cells. Conversely, co-silencing of SNAIL1 and SMAD4 by siRNA inhibited repression of CAR and occludin during EMT. Moreover, loss of CAR and E-cadherin correlated with nuclear co-expression of SNAIL1 and SMAD3/4 in a mouse model of breast carcinoma and at the invasive fronts of human breast cancer. We propose that activation of a SNAIL1-SMAD3/4 transcriptional complex represents a mechanism of gene repression during EMT.

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